Method of treating migraines and pharmaceutical compositions

ABSTRACT

A combination of a 5HT 1B/1D  agonist and a COX-2 selective inhibitor is useful in the treatment and or prevention of migraine.

BACKGROUND OF THE INVENTION

[0001] Migraines are recurrent, often familial, symptom complexes ofperiodic attacks of vascular headache. Migraines affect approximately17% of adult women and 6% of adult men (Stewart et al., Neurology, 1994,44 (suppl. 4), 517-523).

[0002] It has been known for some time that sumatriptan, which causesconstriction of cranial blood vessels, is an effective treatment formigraine (see, for example, Doenicke et al., Lancet, 1988, Vol. 1,1309-11; and Feniuk & Humphrey, Drug Development Research, 1992, 26,235-40). As such, it is the prototypical example of a class ofcompounds, including rizatriptan, which have recently been classified(Hartig et al., TIPS, 1996, 17, 103-105) as 5-HT_(1B/1D) receptoragonists.

[0003] Activation of 5-HT_(1B) and/or 5-HT_(1D) receptors leads to (1)selective vasoconstriction of certain cranial extracerebral blood vesselsegments; (2) pre-junctional inhibition of the release ofproinflammatory neuropeptides from sensory nerve terminals in themeninges; and (3) attenuation of central nociceptive neurotransmissionby inhibition of neurotransmitter release within the trigeminal nucleuscaudalis. It is believed that one or more of these three mechanisms isinvolved in the anti-migraine action of 5-HT_(1B/1D) receptor agonistssuch as rizatriptan.

[0004] Cyclooxygenase (COX), also known as prostaglandin H synthase, isan enzyme implicated in the mediation of pain, fever and inflammation.It catalyzes the oxidative conversion of arachidonic acid intoprostaglandin H₂, a key intermediate in the biosynthetic pathway ofprostaglandins, prostacyclins and thromboxanes, which in turn mediate avariety of physiological effects both beneficial and pathological.Recently it was discovered that two COX isoforms exist: COX-1, expressedconstitutively in many tissues, and COX-2, an induced isoform havingelevated levels of expression in inflamed tissues. COX-1 is thought tobe involved in ongoing “housekeeping” functions, for example, gastriccytoprotection, while COX-2 is implicated in the pathological effectsmentioned above.

[0005] Current cyclooxygenase inhibitors such as aspirin, ibuprofen andindomethacin, used as non-steroidal anti-inflammatory drugs (NSAIDs),inhibit both COX-1 and COX-2 and have associated side effects, such asgastrotoxicity, which may be manifested as ulcer formation. COX-2selective inhibitors act as effective NSAIDs without substantialgastrotoxic side effects. For purposes of this disclosure only, a COX-2selective inhibitor is defined as a COX inhibitor having a selectivityfor the COX-2 isoform relative to the COX-1 isoform.

[0006] The treatment of migraines by coadministration of a 5HT agonistand a traditional analgesic, including a NSAID has been described ininternational patent application WO98/06392.

[0007] It has now been found that migraines can be more effectivelytreated and/or controlled by the co-administration of a 5-HT_(1B/1D)receptor agonist in combination with a COX-2 selective inhibitor, thanwith a 5HT_(1B/1D) agonist alone, and more safely than with atraditional analgesic in combination with a 5HT agonist.

SUMMARY OF THE INVENTION

[0008] The present invention relates to a method of treating orpreventing migraines in a mammalian patient in need thereof, whichcomprises administering to said patient an anti-migraine effectiveamount of a combination of a COX-2 selective inhibitor and a5-HT_(1B/1D) receptor agonist.

[0009] The invention also relates to a pharmaceutical compositioncomprising a COX-2 selective inhibitor, a 5-HT_(1B/1D) receptor agonistand a pharmaceutically acceptable carrier therefore.

DETAILED DESCRIPTION

[0010] One embodiment of the present invention is a method of treatingor preventing migraine with an anti-migraine effective amount of acombination of a 5HT_(1B/1D) agonist and a COX-2 selective inhibitor.Another embodiment of the invention is a pharmaceutical compositioncomprising a combination of a 5HT_(1B/1D) agonist and a COX-2 selectiveinhibitor and a pharmaceutically acceptable carrier.

[0011] In these two embodiments, examples of the 5HT_(1B/1D) agonist canbe selected from rizatriptan (EP 0,497,512), sumatriptan (GB 2,162,522),naratriptan (GB 2,208,646), zolmitriptan (WO91/18897), eleptriptan(WO92/06973), and almotriptan (WO94/02460).

[0012] The preferred 5HT_(1B/1D) agonist for use in this invention isrizatriptan, which isN,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethylamine,the benzoate salt thereof being particularly preferred.

[0013] Examples of COX-2 inhibitors useful in the methods andcompositions described herein include Celebrex® (celecoxib), VIOXX®,MK-663 (WO98/03484), compounds disclosed in WO07/14691, meloxicam, RS57067, valdecoxib (U.S. Pat. No. 5,663,272) and a compound of thestructure:

[0014] In the novel method of treatment described herein, the two activeingredients can be administered combined in a single dosage form such asdescribed as one embodiment of this invention, or as two separate dosageforms, each containing one of the active ingredients, the two beingadministered substantially concurrently.

[0015] In one aspect of the invention, a method of treating orpreventing migraine is disclosed in a mammalian patient in need of suchtreatment, which comprises administering to the patient a COX-2selective inhibiting compound and a 5HT_(1B/1D) agonist, or salts orhydrates thereof, in amounts that are effective for treating orpreventing migraines.

[0016] More particularly, a method is disclosed wherein the 5HT_(1B/1D)agonist is selected from the group consisting of: sumitriptan,naratriptan, zolmitriptan, eleptriptan, almatriptan and rizatriptan andthe COX-2 selective inhibiting compound is selected from the groupconsisting of: meloxicam,2-(6-methylpyrid-3-yl)-3-(4-methylsulfonylphenyl)-5-chloropyridine(MK-663), VIOXX® (valdecoxib), RS 57067, Celebrex® (celecoxib), and acompound of structure:

[0017] Even more particularly, a methodis disclosed wherein the COX-2selective inhibitor is VIOXX® and the 5HT_(1B/1D) agonist is rizatriptanor a salt or hydrate thereof.

[0018] In one aspect, the method is described wherein the 5HT_(1B/1D)agonist and COX-2 inhibitor are administered combined in a single dosageform.

[0019] In another aspect, the method is described wherein the5HT_(1B/1D) agonist and COX-2 inhibitor are administered as separatedosage forms substantially concurrently.

[0020] In a different aspect, a pharmaceutical composition is includedherein which is comprised of a 5HT_(1B/1D) agonist and a COX-2 selectiveinhibiting compound, or salts or hydrates thereof, in combination with apharmaceutically acceptable carrier.

[0021] More particularly, the composition is described wherein the5HT_(1B/1D) agonist is selected from sumitriptan, naratriptan,zolmitriptan, eleptriptan, almatriptan and rizatriptan, and the COX-2inhibitor is selected from MK-663, VIOXX®, meloxicam, RS57067, celoxib,valdecoxib and a compound of structure:

[0022] Even more particularly, the composition is described wherein the5HT_(1B/1D) agonist is rizatriptan or a salt thereof, and the COX-2inhibitor is VIOXX®.

[0023] In a preferred combination, a composition is described whereinrizatriptan or a salt thereof, is present in an amount ranging fromabout 1 to about 10 mg, and VIOXX® is present in an amount ranging fromabout 10 mg to about 100 mg. More particularly, the rizatriptan ispresent as the benzoate salt, and VIOXX.

[0024] An anti-migraine effective amount of the combination is thatamount that will relieve the subject being treated of the symptoms ofthe migraine attack and the specific dose level and frequency of dosagemay vary and will depend upon a variety of factors including theactivity of the specific compounds used in combination, the metabolicstability and length of action of the compounds, the age, body weight,general health, sex diet, mode and time of administration, rate ofexcretion, the severity of the particular condition and the hostundergoing therapy. However, dosage levels of the 5HT_(1B/1D) on theorder of about 0.001 mg/kg to about 250 mg/kg of body weight per day,typically about 0.005 to about 100 mg/kg, more particularly about 0.01to about 50 mg/kg and especially about 0.05 to about 10 mg/kg per dayare useful in the novel method of treatment. Dosage levels of the COX-2inhibitor of about 0.1 to 500 mg/kg of body weight per day, typicallyabout 0.5 to about 250 mg/kg, more particularly about 5 to about 100mg/kg and especially about 10 to about 50 mg/kg of body weight per dayare useful in the novel method of this invention.

[0025] For the treatment of a migraine attack, the active ingredients,separately or in combination, may be administered orally, topically,parenterally, by inhalation, spray, rectally or intravaginally informulations containing pharmaceutically acceptable carriers.

[0026] The term parenteral as used herein includes subcutaneousinjections, intravenous, intramuscular, intrasisternal injection orinfusion techniques.

[0027] The separate active agents or the novel composition of thisinvention may be in a form suitable for oral use, for example, tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsions, hard or soft capsules, solutions, syrups andelixirs. Compositions intended for oral use may be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and typically such compositions contain one or more agentsselected from the group consisting of sweetening agents, flavouringagents, colouring agents and preservatives in order to providepharmaceutically elegant and palatable preparations. These excipientsmay be for example, diluents such as lactose, calcium carbonate, sodiumcarbonate, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch or alginic acid; bindingagents, for example starch, gelatin or acacia, and lubricating agents,for example, magnesium stearate, stearic acid or talc.

[0028] The tablets may be uncoated or they may be coated. Coating can beincluded to delay disintegration and absorption in the gastrointestinaltract and thereby provide a sustained action over a longer period. Forexample, a time delay material such as glyceryl monostearate or glyceryldistearate may be employed. They may also be coated by the techniquedescribed in the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 toform osmotic therapeutic tablets for control release.

[0029] Formulations for oral use may also be presented as hard gelatincapsules wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or miscible solvents such as propylene glycol, PEGs and ethanol,or an oil medium, for example peanut oil, liquid paraffin or olive oil.

[0030] Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethycellulose,sodium alginate, polyvinyl-pyrrolidone, tragacanth and acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl or n-propyl p-hydroxybenzoate, one or more colouringagents, one or more flavouring agents, and one or more sweeteningagents, such as sucrose, saccharin or aspartame.

[0031] Oily suspensions may be formulated by suspending the activeingredient in a vegetable oil, for example arachis oil, olive oil,sesame oil or coconut oil, or in mineral oil such as liquid paraffin.The oily suspensions may contain a thickening agent, for examplebeeswax, hard paraffin or cetyl alcohol. Sweetening agents such as thoseset forth above, and flavouring agents may be added to provide apalatable oral preparation. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

[0032] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example sweetening, flavouring andcolouring agents, may also be present.

[0033] The individual agents or the pharmaceutical compositions of theinvention may also be in the form of oil-in-water emulsions. The oilyphase may be a vegetable oil, for example olive oil or arachis oil, or amineral oil, for example liquid paraffin or mixtures of these. Suitableemulsifying agents may be naturally-occurring phosphatides, for examplesoy bean, lecithin, and esters or partial esters derived from fattyacids and hexitol anhydrides, for example sorbitan monooleate, andcondensation products of the said partial esters with ethylene oxide,for example polyoxy-ethylene sorbitan monooleate. The emulsions may alsocontain sweetening and flavouring agents.

[0034] Syrups and elixirs may be formulated with sweetening agents, forexample glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain demulcents, preservatives, flavourants andcolouring agents.

[0035] The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.

[0036] Injectable compositions are typically in the form of sterilesolutions or suspensions, which include the active ingredient in aparenterally-acceptable diluent. Among these are sterile water, dextrose5% in water (D5W), Ringer's solution and isotonic saline, as well asmixtures thereof. Cosolvents such as ethanol, propylene glycol orpolyethylene glycols may also be used. Sterile, injectable oil isoccasionally employed as a solvent or suspending medium in intramuscularpreparations. A representative example is peanut oil. In addition, fattyacids such as oleic acid, preservatives, buffers and local anestheticsfind use in the preparation of intramuscular injectables.

[0037] The combination of active ingredients may also be administeredrectally or intravaginally as suppositories. These can be prepared bymixing the drug with a suitable non-irritating excipient which is solidat ordinary room temperature but molten at normal or elevated bodytemperature. Examples of such materials include cocoa butter andpolyethylene glycols.

[0038] For topical use, creams, ointments, gels, solutions, suspensionsand the like containing the compound are employed. (For purposes of thisapplication, topical application includes mouth washes and gargles, aswell as transdermal applications.) Topical formulations are comprised ofa pharmaceutical carrier, which may include, e.g., cosolvents,emulsifiers, penetration enhancers, preservatives or emollients.

[0039] The active ingredients are combined with the carrier to producethe dosage form. For example, a formulation intended for oraladministration may contain from as low as about 0.1 mg of the novelcombination to as high as about 5 g of combination per dose, compoundedwith an appropriate and convenient amount of carrier material which mayvary from about 5 to about 95 percent of the total composition.

EXAMPLES 1 AND 2

[0040] Tablet Preparation

[0041] Tablets containing 5 mg and 10 mg of rizatriptan benzoate and 10mg of Vioxx were prepared as follows: Example 1 Example 2 Rizatriptanbenzoate  5.0 mg 10.0 mg Vioxx 10.0 mg 10.0 mg Microcrystallinecellulose 42.0 mg 39.5 mg Modified food corn starch 42.0 mg 39.5 mgMagnesium stearate  1.0 mg  1.0 mg

[0042] All of the active ingredients, cellulose, and a portion of thecorn starch are mixed and granulated to 10% corn starch paste. Theresulting granulation is sieved, dried and blended with the remainder ofthe corn starch and magnesium stearate. The resulting granulation isthen compressed into tablets.

What is claimed is:
 1. A method of treating or preventing migraine in amammalian patient in need of such treatment, which comprisesadministering to the patient a COX-2 selective inhibiting compound and a5HT_(1B/1D) agonist, or salts or hydrates thereof, in amounts that areeffective for treating or preventing migraines.
 2. The method accordingto claim 1 wherein the 5HT_(1B/1D) agonist is selected from the groupconsisting of: sumitriptan, naratriptan, zolmitriptan, eleptriptan,almatriptan and rizatriptan and the COX-2 selective inhibiting compoundis selected from the group consisting of: meloxicam, MK-663, VIOXX®, RS57067, celecoxib, valdecoxib and a compound of structure:


3. The method according to claim 2 wherein the COX-2 selective inhibitoris VIOXX® and the 5HT_(1B/1D) agonist is rizatriptan.
 4. The method ofclaim 1 wherein the 5HT_(1B/1D) agonist and COX-2 inhibitor areadministered combined in a single dosage form.
 5. The method of claim 1wherein the 5HT_(1B/1D) agonist and COX-2 inhibitor are administered asseparate dosage forms substantially concurrently.
 6. A pharmaceuticalcomposition which is comprised of a 5HT_(1B/1D) agonist and a COX-2selective inhibiting compound, or salts or hydrates thereof, incombination with a pharmaceutically acceptable carrier.
 7. Thecomposition of claim 6 wherein the 5HT_(1B/1D) agonist is selected fromsumitriptan, naratriptan, zolmitriptan, eleptriptan, almatriptan andrizatriptan, and the COX-2 inhibitor is selected from MK-663, VIOXX®,meloxicam, RS57067, celoxib, valdecoxib and a compound of structure:


8. The composition of claim 7 wherein the 5HT_(1B/1D) agonist isrizatriptan or a salt thereof, and the COX-2 inhibitor is VIOXX®.
 9. Acomposition in accordance with claim 7 wherein rizatriptan or a saltthereof, is present in an amount ranging from about 1 to about 10 mg,and VIOXX® is present in an amount ranging from about 10 mg to about 100mg.
 10. A composition in accordance with claim 8 wherein the rizatriptanis present in the form of the benzoate salt.